There are many changes in the properties of cells following malignant transformation. We have concentrated on changes in the expression of surface molecules that might represent tumor- specific markers that could be exploited both for diagnosis and therapy of human tumors. Using hybridoma technology and morphologic methods, we have isolated monoclonal antibodies to surface epitopes on human tumor cells. One of these antibodies, B3, has recently been studied in detail. This antibody has been shown to react with a specific area of the Lewis(Y) antigen structure. This antibody reacts with some normal tissues, such as gastric and bladder epithelium, as well as human tumors of colon, ovarian and breast origin. Recently, a conjugate of B3 with Pseudomonas exotoxin (PE) has been shown to be effective in killing target tumor cells in tissue culture, as well as in an animal model in nude mice using both A431 and MCF-7 human tumor cells. The absence of serious tissue-specific toxicity in preclinical testing in monkeys suggest that B3 may be useful for therapy of some human cancers. Another antibody, Kl, reactive with ovarian tumors and normal mesothelium has been characterized. It reacts with an antigen that is coexpressed frequently with the CA125 antigen, but it does not react with purified CA125. The antigen reactive with KI (CAK1) is not shed from the surface of cells, yet it is released from cells treated with phospholipase C. CAK1 has been partially purified and appears to be a protein of approximately 40 kD. An immunotoxin prepared using Kl is effective in killing target cells in tissue culture. In other studies, a morphologic assay for the monomer-tetramer conversion of pyruvate kinase Ml in intact cells was developed; this enzyme is a major binding protein for thyroid hormone in the cytoplasm of cells. Also, other studies of a transgenic mouse line developed using the human EGF receptor gene showed that these mice have a defect in microtubule stability in the axoneme of sperm in homozygous animals.